3-benzyl-4-lower-alkyl-3, 4, 5, 6-tetrahydro-4-carboline quaternary ammonium salts and preparation thereof



Unite This invention relates to new 3-benzyl-4-lower-alkyl-3,4,5,6-tetrahydro-4-carboline quaternary ammonium salts and to methodsfor the preparation thereof.

The compounds of the invention are quaternary ammonium salts ofcompounds having the formula wherein Ar is monocarbocyclic ortho-aryleneand R is loWer-alkyl.

A preferred aspect of the invention relates to pounds having the formula8 7 R3 R1 R4 1 2H i E 13 W \m H CH2 wherein R represents lower alkyl; Rrepresents loweralkyl, hydroxy-lower-alkyl, loWer-alkenyl ormonocarbocyclic aryl lower-alky]; An represents an anion from an ester,R An, of a strong acid; and R and R each represents hydrogen or from oneto two substituents selected from the group consisting of halogen(including fluorine, chlorine, bromine and iodine), lower-alkyl,loweralkoxy, hydroXy, methylene-dioxy, loWer-alkylmercapto,lower-alkylsulfinyl, loWer-alkylsulfonyl and lower-alkanoyloxy.

In the above general Formula '11, R represents loweralkyl which can beeither straight or branched and can contain from one to about fourcarbon atoms. R thus stands, inter alia, for methyl, ethyl, propyl,isopropyl, n-butyl, and the like.

In the above general Formula 11, R represents loweralkyl,hydroxy-lower-alkyl, lower-alkenyl or monocarbocyclic aryl-loWer-alkyl;and An represents the anion of an ester of a strong acid, for example aninorganic acid or an organic sulfonic acid. Thus R An together representloWer-alkyl, hydroXy-loWer-alkyl, lower-alkenyl or monocarbocyclicaryl-lower'alkyl esters of said inorganic acids or organic sulfonicacids. erably have a molecular Weight less than about 250. Thus R Antogether represent such compounds, inter alia, as methyl chloride,methyl bromide, methyl iodide, ethyl bromide, propyl chloride, isopropylchloride, n-butyl iodide, 2-hydroxyethyl bromide, allyl chloride, allylbromide, methyl sulfate, methyl benzenesulfonate, methyl Said esterspref- States Patent Ofifice Patented Jan. 1, 1053 Girlp-toluenesulfonate, benzyl chloride, benzyl bromide, pchloro-benzylchloride, p-nitrobenzyl chloride, o-cnlorobenzyl chloride,-p-methoxybenzyl chloride, and the like.

In the above general Formula II, R and R each represents hydrogen or asubstituent selected from the group consisting of halogen (includingfluorine, chlorine, bromine and iodine), lower-alkyl, loWer-alkoxy,hydroxy, methylenedioxy, loWer'alkyl-mercapto, loWer-alkylsulfinyl,loWer-alkylsulfonyl and loWer-alkanoyloxy. When R and R represent one ofthe above substituents, said substituents can be on any of the fouravailable positions of the benzene ring, and when more than onesubstituent is present, they can be the same or different. When R or Rrepresents loWer-alkyl, lower-alkoxy, loWer-alkyimercapto,lower-alkylsulfinyl, lower-alkylsulfonyl, or loWer-alicanoyloxy, theycan be straight or branched and can contain from one to about fourcarbon atoms. R and R thus stand, inter alia, for fluorine, chlorine,bromine, iodine, methyl, ethyl, butyl, methoxy, dimethoxy, ethoxy,ethoXy-methoxy, hydroXy, methylenedioxy, methylmercapto, methylsulfinyl,methylsulfonyl, isopropylmercapto, isopropylsulfinyl, isopropylsulfonyl,acetoxy, and the like.

The compounds of the invention are prepared by the following reactionsin which R R R R and Anhave the meanings given above.

III

+ CuHsCHzC O G O OH lCaH CH2CHO A tryptamine of Formula III is reactedwith phenylpyruvic acid at a temperature between about 50 C. and about150 C. in a solvent inert under the conditions of the reaction, forexample water, methanol, ethanol and ethylene glycol to give thecompounds of Formula IV. A preferred solvent is Water.

The resulting 3-benzyl-3,4,5,6-tetrahydro-4-carboline- 3-carboxylicacids of Formula IV thus produced are then decarboxylated to thecorresponding 3-benzyl-3,4,5,6- tetrahydro-4-carbolines of Formula V byheating the former at a temperature in the range from about 50 C. toabout C. with a strong mineral acid, for example hydrochloric acid,hydrobromic acid, sulfuric acid, phos phoric acid and the like. Thereaction is preferably carried out in an organic solvent inert under theconditions of the reaction, for example methanol, ethanol, isopropanol,ethylene glycol, and the like. A preferred mineral acid is hydrochloricacid, and a preferred solvent is methanol.

Alternatively the compounds of Formula V can be prepared by reacting atryptamine with phenylacetaldehyde :at a temperature in the range fromabout 50 C. to about 150 C. in the presence of a strong mineral acid,for example hydrochloric acid, sulfuric acid, phosphoric acid and thelike, thus giving the compounds of Formula V directly. The reaction ispreferably conducted in a solvent inert under the conditions of thereaction, for example water, methanol, ethanol and the like. A preferredmineral acid is sulfuric acid and a preferred solvent is water.

Compounds of Formula II, where R and R are the same lower-alkyl, can beprepared by reacting the 3- benzyl-3,4,5,6-tetrahydro-4-carbolines ofFormula V in the presence of an acid-acceptor with at least two molarequivalents of a lower-alkylating agent, for example loweralkyl estersof strong acids. Preferred lower-alkylating agents are lower alkylsulfates, lower-alkyl halides and lower-alkyl p-toluenesulfonates. Thereaction is preferably carried out at a temperature in the range fromabout 50 C. to about 100 C. in the presence of an acid-acceptor and inan organic solvent inert under the conditions of the reaction, forexample methanol, ethanol, isopropanol, ethylene glycol and the like.

The purpose of the acid-acceptor is to take up the hydrogen halideproduced when a lower-alkyl halide is the lower-alkylating agent, or thelovver-alkyl acid sulfate or sulfuric acid produced when a lower-alkylsulfate is the loWer-alkylating agent, or the p-toluenesulfonic acidproduced when a lower-alkyl p-toluenesulfonate is the lower-alkylatingagent. The acid-acceptor includes such substances as alkali metalcarbonates, for example sodium and potassium carbonate and alkali metalhydroxides, for example sodium hydroxide and potassium hydroxide. Apreferred lowver-alkylating agent is a loweralkyl halide, and it ispreferred to carry out the reaction in methanol using sodium carbonateas the acid-acceptor.

Alternatively, the 3-benzyl-3,4,5,6-tetrahydro4-carbolines of Formula V,prepared by either of the methods described above, can be reacted withone molar equivalent amount of a lower-alkylating agent, for example alower-alkyl sulfate, a lower-alkyl halide or a lower-alkylp-toluenesulfonate, in the presence of a molar equivalent amount of anacid-acceptor at a temperature in the range from about 50 C. to about100 C. to give the corresponding3-benzyl-4-lower-alkyl-3,4,5,6-tetrahydro-4-carbolines of Formula VI.The reaction is preferably carried out in an organic solvent inert underthe conditions of the reaction, for example methanol, ethanol,isopropanol, ethylene glycol, and the like. The purpose and nature ofthe acid-acceptor are the same as described above for the directpreparation of the compounds of Formula II from the compounds of FormulaV.

The compounds of Formula II can then be prepared from the resulting3-benzyl-4-lower-alkyl-3,4,5,6-tetrahydro-4-carbolines by mixing thelatter with the lower-alkyl, hydroxy-lower-alkyl, lower-alkenyl ormonocarbocyclic aryl-lower-alkyl ester in an organic solvent for examplemethanol, ethanol, acetonitrile, acetone and the like. Heating can beused to facilitate the reaction although salt formation generally takesplace readily at room temperature. The compounds of Formula II separatedirectly or can be obtained by concentration of the solution. Thisprocedure afiords compounds of Formula II wherein both R and R areeither the same or different lower-alkyls or where R representslower-alkyl and R represents either lower-alkenyl, hydroxy-lower-alkylor monocarbocyclic aryl-lower-alkyl.

The tryptamines used as starting material in the abovedescribedprocedures are prepared by known methods, for example by the Fischerindole synthesis using an appropriate phenylhydrazine and a'y-phthalimidobutyraldehyde. The resultingB-(Z-phthalimidoethyl)indoles, on hydrolysis with hydrazine hydrate,afford the desired tryptamines.

Alternatively, the starting tryptamines can be prepared by reacting anindole with formaldehyde and a di-loweralkyl amine, for exampledimethylamine, to give a 3-diloWer-alkylaminomethylindole. The latter,on reaction with hydrocyanic acid, gives the corresponding3-cyanomethylindole which on catalytic reduction with, for example,palladium-on-charcoal affords the desired tryptamine.

Another method for preparing the starting tryptamines comprises reactingan indole with a glyoxalyl halide to give a 3-(indolyl)glyoxalyl halide.The tryptamines are obtained by reacting the 3-(indolyl)glyoxalylchloride with ammonia and reducing the resulting 3-(indolyl)glyoxamideWith an alkali metal aluminum hydride, for example lithium aluminumhydride.

The quaternary ammonium salts of the invention possess a depressantaction on the central nervous system, they lower the blood pressure, andthey possess monoamineoxidase inhibition activity. These propertiesindicate their usefulness as hypotensive agents and as psychicenergizers.

Preferred quaternary ammonium salts are water-solu ble and are the formin which the compounds are conveniently prepared for pharmacologicaluse. Pharmacologically acceptable salts are salts Whose anions areinnocuous to the animal organism in effective doses of the salts, sothat beneficial physiological properties inherent in the free bases arenot vitiated by side-effects ascribable to the anions; in other words,the latter do not substantially affect the pharmacological propertiesinherent in the cations.

Although pharmacologically acceptable salts are preferred, those havingtoxic anions are also useful in preparing pharmacologically acceptablesalts by ion exchange procedures.

The structures of the compounds of the invention have been establishedby chemical analysis and by the processes for their preparation, whichcan only lead to compounds .of the assigned structures.

The following examples will further illustrate the invention, withoutthe latter being limited thereto.

EXAMPLE 1a 3-Benzyl-3,4,5,6-Tetrahydr0-4-Carboline-3-Carb0xylic Acid[IV; R, and R are H] -Tryptamine hydrochloride (5.85 g., 0.036 mole) andphenylpyruvic acid (6.0 g., 0.037 mole) were separately dissolved in ml.of water with warming. The solutions were cooled, combined and thecombined solution heated on a steam bath for about thirty hours. Whencooled, the product separated and was collected by filtration giving 8.6g. of 3-benzyl-3,4,5,6 tetrahydro-4-carboline-3-carboxylic acid, M.P.226-232" C. (uncorr.).

EXAMPLE lb which separated was collected and dried giving 5.5 g. of3-benzyl-3,4,5,6-tetrahydro-4-carboline hydrochloride, MP. 271272 C.(uncorr).

Anal.Calcd. for C H N .HCl: N, 9.77. Found:

The compounds can be prepared for use by dissolving the salts understerile conditions in water or in a physiologically compatible aqueousmedium such as saline, and stored in ampules for intramuscularinjection. Alterna- N, 9.06. 5 tively they can be formulated in unitdosage form as The 3-benzyl-3,4,5,6-tetrahydro-4-carbolinehydrochlotablets for oral administration in combination with suitrideobtained above was converted to the free base, and able adjuvants suchas calcium carbonate, starch, lactose, 2.8 g. (0.011 mole) of the basewas dissolved in 25 ml. talc, magnesium stearate, gum acacia, and thelike. A1- of methanol. To the solution was added 3.0 g. (0.028ternatively they can be employed in capsule form either mole) of sodiumcarbonate and 5 ml. of methyl iodide. alone or admixed with an adjuvant.Still further, the The mixture was heated under reflux for twenty-onecompounds can be formulated for oral administration as hours, cooled andthe precipitated solid collected. The aqueous alcohol solutions, oilsolutions or oil-water emulsolid was recrystallized from water giving3.3 g. of 3-bensions in the same manner as conventional medicinalsubzyl-4-rnethyl-3,4,5,6-tetrahydro 4 carboline methiodide, stances areprepared. MP. 206.4207.3 C. (corr.). I claim:

AnaL-Calcd. for C H N E: C, 57.42; H, 5.54; N, 1. A compound having theformula 6.70. Found: C, 57.67; H, 6.49; N, 5.34.

EXAMPLE 2a R 3-BenzyZ-11-Metho:dy-3,4,5, 6-Tetrahydr0-4-Carb0line E I IX [V; R is 11CH O, R is H] 4 N/\+/N\ An- By reacting 6-methoxytryptaminewith a molar equiv- I I alent amount of phenylacetaldehyde in an aqueousme- E dium in the presence of sulfuric acid, there can be ob- O tained3-benzyl 11 methoxy-3,4,5,6-tetrahydro-4-carboline.

EXAMPLE 212 3 Benzyl 11 i aggi g et'a y m wherein R 1s lower-alkyl; R isa member of the group 1 consisting of loWer-alkyl, hydroxy-lower-alkyl,lower- [E 1 13 3; 2 2= 2: 3 15 3 alkenyl and monocarbocyclic aryllower-alkyl; R and R s 15 H, Air 15 BF] each is a member of the groupconsisting of hydrogen, By reacting the 3-benyl-l1-methcXy-3,4,5,6-tetrd halogen, lower-allcyl, lower-allcoxy, hydroxy, methylene- 4-carbolineobtained above in Example 2a with one Y, lower-alkylmercapto:lower'alkylsulfulyb w molar equivalent amount of methyl sulfate in thepresence alkylsulfonyl and loweljalkanoyloxy; and 35 an amonof sodiumcarbonate in an appropriate solvent, for ex- A Compgund havmg thelormula ample ethanol, there can be obtained3-benzyl-1l-methoxy-4-methyl-3,4,5,6-tetrahydro-4-carboline By reactingthe latter with allyl bromide in an appropriate organic 40 R1 solvent,for example ethanol, there can be obtained 3-ben- Ar zyl llmethoxy4-methyl-3,4,5,6-tetrahydro-4-carboline /Y allobromide. I

H CH2 EXAMPLES 3-22 1 By following one of the manipulative proceduresdescribed above in Examples 1 and 2, substituting for the reactants usedtherein the appropriate tryptamine, the appropriate lower-alkylatingagent and the appropriate 0 lower-alkyl, hydroxy-lower-alkyl,lower-alkenyl or mono- 0 carbocyclic aryl-lower-alkyl ester of a strongacid, there Wherem 1 and R2 are lower'alkyl and An 1S an f can beobtained the compounds of Formula II listed be- 3 Y 4methyl-3,4.5.fi-tetfahydfo'4-carbolme low in Table I. methiodide.

TABLE I R1 R2 An R3. 4

10-F 10-01 10-131 10-1 l2-OH3 12-02115 121'1-O4H9 9 01130 10,11di-OH3Oson-I l0'C2H O-1l-GHsO 11-HO 10,11-001120 ll-CHsS o ll-CHsSO p-ClCsHsCHzin U ll-CHaSO D-NO2C5H4OI'I2 11-(CH3)2CHS o-oio u ortzh u-(oumoHso-ornoofiuiomw ll-tCHalzOHSO: 3,4-OlgCaH3OH2 1l-OH3GOO 4. The process forpreparing a compound having the alkylsulfonyl and lower-alkanoyloxy; andAn is an anion which comprises reacting a compound having the formulaCH: CHZNH] Rs R. l

with phenylpyruvic acid, decarboxylating the resulting 3-benzyl-3,4,5,6-tetrahydro-4-carboline-3-carboxylic acid by heating itwith a strong mineral acid; reacting the resulting3-benzyl-3,4,5,6-tetrahydro-4-carboline with one molar equivalent amountof a lower-alkylating agent in the presence of an acid-acceptor, andreacting the resulting 3 benzyl 4 loweralkyl-3,4,5,6tetrahydro-4-carboline with an ester, R An, of a strongacid wherein R and R have the meanings given above.

5. The process for preparing a compound having the formula wherein R andR are lower-alkyl, and Anis an anion which comprises reacting tryptaminewith phenylpyruvic acid, decarboxylating the resulting3-benzyl-3,4,5,6-tetrahydro-4-carboline-3-carboxylic acid by heating itwith a strong mineral acid, and reacting the resulting 3-benzyl-3,4,5,6-tetrahydro-4-carboline in the presence of an acidacceptor withat least two molar equivalents of a loweralkyl ester of an inorganicacid.

6. The process for preparing 3-benZyl-4-methyl-3,4,5,6-tetrahydro-4-carboline methiodide which comprises reacting tryptaminewith phenylpyruvic acid, decarboxylating the resulting3-benzyl-3,4,5,6-tetrahydro-4-carboline- 3-carboXylic acid by heating itwith hydrochloric acid, and reacting the resulting3-benzyl-3,4,5,6-tetrahydro-4- carboline in the presence of anacid-acceptor with at least two molar equivalents of methyl iodide.

References Cited in the file of this patent UNITED STATES PATENTS2,642,438 Duschinsky June 16, 1953 2,819,998 McLamore Ian. 14, 19582,852,520 Robinson Sept. 16, 1958 OTHER REFERENCES Hahn et al.: Berichteder Dent. Chem. GeselL, vol. 67B, pp. 2031-2035 (1934).

Hoshino: Chemical Abstracts, Vol. 29, pp. 2956 (1935).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,071,589 January 1, 1963 Sydney Archer It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 1, lines 32 to 42, below the formula insert II column 2, lines 35to 45, formula IV should appear as shown below instead of as inthe'patent:

column 5, line 42, for "methoxy4methyl" read methoxy-4- methyl column 6,lines 34 to 36, for "me'thylenethloxy loweralkylmercapto,lower-alkylsulfinyl, lower-alkylsulfonyl and lower-alkanojzloxyfi' readlower-alkylmercapto, lower alkylsulfinyl, lower-alkylsulionyl andloweralkanoyloxy, and R and R together are methylenedioxy; column 7,lines 19 to 21, for "methylenedioxy, lowe r-alkylmercapto, lowera lkylsulfinyl, lower-alkylsulfonyl and lower-alkanoyloxy readlower-alkylmercapto, lower-alkylsulfinyl, loweralkylsulfonyl andlower-alkxnoyloxy, and R and R together are methylenedioxy;

Signed and sealed this 24th day of December 1963.

(SEAL) Attest: ERNEST W. SWIDER EDWIN L, REYNOLDS Attesting OfficerActing Commissioner of Patents

1. A COMPOUND HAVING THE FORMULA